The broad, long-term objective of this proposal is to elucidate the mechanisms by which specific stress proteins reduce oxidative damage, and to develop strategies by which the heat shock family of stress proteins can protect and enhance the physiological recovery of the post- ischemic heart. The central hypotheses to be tested are (i) that the rapid synthesis of the cardioprotective stress proteins during ischemia is dependent on the regulatory heat shock transcription factor, HSFI, and (ii) that the various members of the heat shock family of stress proteins are functionally heterogenous in their capacity to ameliorate oxidative stress/damage and thereby, the speed of the physiological recovery of myocardial cells, which have sustained reversible ischemic damage. Transgenic approaches, using gene knockout and conditional null alleles in mouse models, will be used to establish whether or not a direct causal relationship exists between stress protein gene induction and ischemic cardioprotection in vivo. Miniaturized techniques for NMR spectroscopy and imaging in the mouse will be used to determine cardiac function and metabolism of the post-ischemic heart. The following three specific aims are designed to test these hypotheses: Specific aim 1: Determine whether or not the loss of function of stress-inducible heat shock protein synthesis accelerates the onset and/or progression of ischemic myocardial injury through increases in oxidative stress/damage of the intact post-ischemic heart. Specific aim 2: Determine whether or not loss of function of heat shock protein synthesis impairs metabolic recovery and increases ventricular dysfunction of the intact post-ischemic heart. Specific aim 3: Establish whether gain of function of specific stress proteins, under the control of an inducible-system, will rescue ischemic susceptibility of HSF1 deficient mice through effects that ameliorate oxidative damage, enhance cardiac metabolism, and restore ventricular function.